Influenza is an acute, contagious respiratory disease caused by influenza viruses which is spread through respiratory droplet transmission. Uncomplicated influenza is characterized by the abrupt onset of constitutional and respiratory symptoms which usually resolve within a week. In certain persons, influenza can aggravate existing medical conditions and potentially lead to life-threatening complications. Influenza viruses are one of the most ubiquitous viruses present in the world, affecting both humans and livestock. Influenza also has a significant impact on the elderly and on the very young. Influenza results in an economic burden, morbidity and even mortality, which are significant.
Influenza viruses are enveloped negative-sense RNA viruses with a segmented genome belonging to the Orthomyxoviridae family. They are classified on the basis of their core proteins into three distinct types: A, B, and C [Cox N J, Fukuda K. Influenza. Infect. Dis. Clin. North Am. 1998; 12:27-38]. Influenza A viruses can infect a range of mammalian and avian species, whereas types B and C are essentially restricted to human beings. Influenza A and B viruses are mainly responsible for human disease with type A being the most pathogenic. The main antigenic determinants of influenza A and B viruses are two surface glycoproteins: neuraminidase (NA) and hemagglutinin (HA), both capable of eliciting immune response in human beings. HA is involved in receptor binding and membrane fusion. NA facilitates cleavage of virus progeny from infected cells, prevents viral aggregation, and aids movement through the mucosal respiratory-tract epithelium.
Virus strains are classified according to host species of origin, geographical site, year of isolation, serial number, and, for influenza A, by serological properties of HA and NA subtypes. Sixteen HA subtypes (H1-H16) and nine NA subtypes (N1-N9) have been identified for influenza A viruses [Webster R G et al. Evolution and ecology of influenza A viruses. Microbiol. Rev. 1992; 56:152-179; Fouchier R A et al. Characterization of a Novel Influenza A Virus Hemagglutinin Subtype (H16) Obtained from Black-Headed Gulls. J. Virol. 2005; 79:2814-2822). Viruses containing all HA and NA subtypes have been recovered from aquatic birds, but only three HA subtypes (H1, H2, and H3) and two NA subtypes (N1 and N2) have established stable lineages in the human population since 1918. Only one subtype of HA and one of NA are recognised for influenza B viruses.
Interpandemic influenza vaccines are currently mainly prepared from virus that is grown in fertile hens' eggs and are either inactivated or live attenuated influenza vaccine. Inactivated flu vaccines are composed of three possible forms of antigen preparation: inactivated whole virus, sub-virions where purified virus particles are disrupted with detergents or other reagents to solubilise the lipid envelope (so-called “split” vaccine) or purified HA and NA (subunit vaccine). These inactivated vaccines are currently given intramuscularly (i.m.), subcutaneously (s.c), or intranasally (i.n.). In accordance with World Health Organization (WHO) recommendations, seasonal influenza vaccines usually contain 45 μg of HA antigen from three co-circulating human strains (as measured by single radial immunodiffusion (SRD) (J. M. Wood et al.: An improved single radial immunodiffusion technique for the assay of influenza haemagglutinin antigen: adaptation for potency determination of inactivated whole virus and subunit vaccines. J. Biol. Stand. 5 (1977) 237-247; J. M. Wood et al., International collaborative study of single radial diffusion and immunoelectrophoresis techniques for the assay of haemagglutinin antigen of influenza virus. J. Biol. Stand. 9 (1981) 317-330)). They generally contain antigens derived from two influenza A virus strains and one influenza B strain (e.g. H1N1, H3N2 and B). A standard 0.5 ml injectable dose in most cases contains (at least) 15 μg of haemagglutinin antigen component from each strain.
Vaccination plays a critical role in controlling annual influenza epidemics. Furthermore, during a pandemics, antiviral drugs may not be sufficient or effective to cover the needs and the number of individuals at risk of influenza will be greater than in interpandemic periods, therefore the development of a suitable vaccine with the potential to be produced in large amounts and with efficient distribution and administration potential is essential. Therefore, in the event of pandemics, vaccination will be instrumental in the strategy to protect the human population from a newly emerging pandemic influenza strain. Therefore, rapid development of a pandemic vaccine is of particular urgency. Means to reduce the severity of the pandemics when it occurs are still needed. Prevention and control of the pandemics will largely depend on the rapid production and worldwide distribution of strain-specific pandemic vaccines.
Besides the need to develop effective candidate ‘pandemic-like’ vaccines or “pre-pandemic” vaccines, there is a crucial need to develop effective and appropriate vaccination strategies, in order to protect immunologically naïve people, and ultimately an immunologically naïve population, against influenza illness and fatality. In particular there is a need to develop appropriate vaccination strategies 1) to protect the workers involved in the production of a vaccine derived from a highly pathogenic avian virus, or 2) to rapidly protect vulnerable populations such as the pediatric or the elderly population against seasonal or pandemic influenza virus.